Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer
Introduction
The standard treatment for fit patients with advanced non-small-cell lung cancer (NSCLC) has been platinum-based chemotherapy [1], [2], [3], [4], [5]. Since almost all patients with advanced NSCLC will suffer from progression of their disease, one of the ultimate goals of palliative chemotherapy is prolongation of overall survival (OS) as well as improvement of symptoms and quality of life. Until now, evaluation of the efficacy of treatment strategies as well as approval of most new agents for advanced NSCLC has been based on prolongation of OS.
Progression-free survival (PFS) is defined as the time elapsed between treatment initiation and tumor progression or death from any cause [6]. PFS captures tumor shrinkage, stabilization, and their duration, all of which are essential for evaluation of new agents, despite several limitations of PFS including measurement error and evaluation time bias [7].
Recently, several agents have been shown to be active in the salvage setting for advanced NSCLC [8], [9], [10], [11], [12], including molecular-targeted agents [13], that have demonstrated dramatic tumor shrinkage even in pre-treated patients with tolerable toxicities. However, their dramatic response and prolongation of PFS frequently have not been accompanied by significant, or any, prolongation of OS, possibly due to crossover and the effects of subsequent therapies. In several cancers including colon cancer, new drugs now are approved based on response and PFS endpoints. With survival advantages now documented for first-, second- and even third-line therapy for NSCLC many oncologists feel that the time has come to approve new drugs for NSCLC on the basis of PFS.
Our previous study showed that, in trials in which patients, upon completion of one treatment, are switched to the treatment in the other arm (crossover trials [14]), there was a poor association between PFS- and OS-hazard ratios (HRs) [15]. In contrast, there was indeed a strong association between the two HRs in trials in which crossover after disease progression was not allowed. However, even if crossover to the investigational agent/regimen is prohibited in a protocol, many other options are now available to patients; use of these treatments may vary from trial to trial, and may not be balanced between the original study arms. To date, few studies have addressed whether and how subsequent therapies affect the association between PFS and OS in NSCLC. Thus, we performed this literature-based review to create a database of phase III trials of molecular-targeted agents for advanced NSCLC, with the aim of clarifying the impact of crossover therapies and other post-study chemotherapy on the PFS–OS association in these trials.
Section snippets
Search for trials
We conducted a literature search of trials reported between January 1991 and November 2010. To avoid publication bias, both published and unpublished trials were identified through a computer-based search of the PubMed database and abstracts from the past conferences of the American Society of Clinical Oncology, European Society for Medical Oncology, and International Association for the Study of Lung Cancer. We used the following search terms: “lung neoplasm”, “carcinoma”, “non-small-cell”,
Trials demographics
Of the 3388 trials screened, 34 phase III trials (Appendix Table 2 and web-appendix [online only]), investigating 15 types of molecular-targeted agents and involving 27,373 patients with advanced NSCLC, were identified as having data regarding PFS- and OS-HRs (Fig. 1). After exclusion of 3215 patients for various reasons in the 34 trials, the remaining 24,158 patients were randomly allocated to 69 arms. Among the 34 trials, one had three arms [22], resulting in 35 pairs of the investigational
Discussion
We investigated the potential influence of post-study therapy including crossover therapy on the association between PFS and OS. Our study shows, that, overall, there is little correlation between PFS- and OS (R2 = 0.1428; Fig. 2A) in the entire study, whilst better correlation was observed in the small subset of studies that did not permit crossover (R2 = 0.6925; Table 2). In contrast, the association became less clear once patients were allowed to cross over.
The main advantage of a randomized
Conclusion
We have demonstrated, even in advanced NSCLC, a strong association between PFS and OS in the circumstances where post-study treatments were seldom employed. However, with more and more active agents available even in salvage settings, increasingly longer SPP is to be expected even in advanced NSCLC, which could weaken the original association. Indeed, in most situations, crossover treatment and intensive post-study treatments may be unavoidable in view of the patient benefit and ethics. Thus,
Conflict of interest statement
KH has received honoraria from Eli Lilly Japan, Nihon Kayaku, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical and Sanofi-Aventis. MD has received honoraria from Eli Lilly Italy. NT has received honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical and Sanofi-Aventis. MR has received honoraria from Hoffmann-La Roche, Lilly, Merck and AstraZeneca, and hold consultant or advisory role for Lilly, Pfizer, Bristol Meyers Squibb, Daiichi Pharmaceutical and AstraZeneca. FA holds
Funding sources and any writing assistance
None declared.
Acknowledgements
We wish to thank Dr Lesley Seymour for the support and comments on our analyses.
The interpretation and reporting of these data are the sole responsibility of the authors. KH had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. KH, ES, and YF contributed to the study design, data collection, analyses, and manuscript writing. All the other co-authors contributed to manuscript writing.
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